1. Field of Art
Disclosed herein are solid fixed-dose pharmaceutical dosage forms that include carbidopa, levodopa, and entacapone, or their pharmaceutically acceptable salts, solvates, or hydrates thereof, and methods of preparing the pharmaceutical dosage forms. The dosage forms can be used, for example, in the treatment of Parkinson's disease.
2. Description of Related Art
Carbidopa, levodopa, and entacapone are therapeutic agents that are used to treat Parkinson's disease. Parkinson's disease is related to the depletion of dopamine. Levodopa (L-DOPA, or L-3,4-dihydroxyphenylalanine) is an aromatic amino acid derivative that is converted into dopamine in the body and increases dopamine levels. Unlike dopamine, levodopa is able to cross the blood-brain barrier. Therefore, administration of levodopa and its subsequent conversion to dopamine in the brain will increase dopamine levels in the brain. Administration of dopamine will not increase dopamine levels in the brain because dopamine does not cross the blood-brain barrier.
Carbidopa inhibits the decarboxylation of aromatic amino acids and inhibits the decarboxylation of levodopa into dopamine. Coadministration of carbidopa and levodopa results in increased plasma concentration of levodopa and improved efficacy. The uncarboxylated levodopa can be more readily absorbed into the brain and converted into dopamine. Coadministration of carbidopa and levodopa also increases the plasma half life of levodopa.
Entacapone is a peripherally acting selective and reversible inhibitor of catechol-O-methyltransferase (COMT). COMT metabolizes levodopa into 3-methoxy-4-hydroxy-L-phenylalanine. Therefore, administration of entacapone with levodopa prevents the degradation of levodopa and further increases its efficacy. When entacapone is dosed with carbidopa and levodopa the plasma levels of levodopa are greater and more sustained than administration of carbidopa and levodopa alone. The half life of levodopa is also increased. It is believed that increased plasma levels of levodopa leads to more constant dopaminergic stimulation in the brain and improved treatment of Parkinson's disease. As used herein, carbidopa, levodopa, and entacapone refer to the compounds as well as any salts, hydrates, or solvates thereof.
Due to the relationship between levodopa, carbidopa, and entacapone they are often dosed together. For example, the commercially available dosage forms PARCOPA® and SINEMET® include carbidopa and levodopa, while the dosage form COMTAN® includes entacapone. Each of the dosage forms are used to treat Parkinson's disease. The commercially available dosage form STALEVO® contains all three compounds in one dosage form and is used to treat Parkinson's disease.
STALEVO® is a replacement for individual carbidopa/levodopa and entacapone products and is described by U.S. Pat. No. 6,500,867 (“the '867 patent”). The '867 patent discloses a single dosage form that includes each of carbidopa, levodopa, and entacapone. According to the specification, the bioavailability of the dosage form is increased when a substantial portion of carbidopa is added separately to levodopa and entacapone. The carbidopa can be added to the formulations of the '867 patent as granules or as a powder that is distinct from the granules or powder containing levodopa and entacapone. A substantial portion of the carbidopa is separated from the entacapone and levodopa when levodopa and entacapone are mixed separately and then carbidopa is added to the mixture of levodopa and entacapone.
The '867 patent teaches that microcrystalline cellulose should not be used as an excipient. According to Example 1 of the '867 patent, when a formulation is prepared by wet granulating carbidopa, levodopa, and entacapone together and adding microcrystalline cellulose the bioavailability of the resulting composition is lower than pharmaceutically acceptable. An acceptable bioavailability may be 80-125% of the bioavailability of STALEVO® for a given pharmacokinetic parameter, such as AUCL or CPEAK. A different formulation can be prepared by dry granulating carbidopa, levodopa, and entacapone. However, the dry granulated formulation is unstable when microcrystalline cellulose is used as an excipient. According to the specification, microcrystalline cellulose destabilizes carbidopa/levodopa/entacapone compositions that contain all three compounds when the formulation is stored for a long term.
U.S. Published Patent Application No. 2006/0222703 (“the '703 publication”) also discloses a formulation that includes each of carbidopa, levodopa, and entacapone. However, the formulation is prepared using a “solvent free” method of mixing the compounds. According to the '703 publication wet granulating levodopa, carbidopa, and entacapone leads to unacceptable stability of the resulting dosage form. The document states that a wet granulated dosage form containing carbidopa, levodopa, and entacapone is unacceptably large in size. PCT Publication No. WO 2009/098661 discloses a formulation containing each of carbidopa, levodopa, and entacapone where the entacapone is added to the formulation by comicronizing entacapone with a sugar alcohol.
None of the formulations discussed above are prepared by wet granulation of a mixture of carbidopa, levodopa, and entacapone together, resulting in a stable composition with a pharmaceutically acceptable bioavailability. Therefore, there is a need for a stable pharmaceutical composition that is prepared by wet granulation of carbidopa, levodopa, and entacapone, wherein the compounds are mixed together before incorporation into the dosage form.